Gap-43 protein

Growth Associated Protein 43 (GAP43) is a protein encoded by the GAP43 gene^[5] in humans.

GAP43 is called a "growth" or "plasticity" protein because it is expressed at high levels in neuronal growth cones during development^[6] and axonal regeneration, and it is phosphorylated after long-term potentiation and after learning.^{[citation needed]}

GAP43 is a crucial component of the axon and presynaptic terminal. Its null mutation leads to death within days after birth, due to axon pathfinding defects.^[7]

Synonyms

GAP43 is also referred to as:

• protein F1
• neuromodulin
• neural phosphoprotein B-50
• axonal membrane protein GAP-43
• calmodulin-binding protein P-57
• nerve growth-related peptide GAP43
• neuron growth-associated protein 43

Function

GAP43, is a nervous tissue-specific cytoplasmic protein that can be attached to the membrane via a dual palmitoylation sequence on cysteines 3 and 4. This sequence targets GAP43 to lipid rafts. It is a major protein kinase C (PKC) substrate and is considered to play a key role in neurite formation, regeneration, and plasticity.^[8][9] The role of GAP-43 in CNS development is not limited to effects on axons: It is also a component of the centrosome, and differentiating neurons that do not express GAP-43 show mislocalization of the centrosome and mitotic spindles, particularly in neurogenic cell divisions. As a consequence, in the cerebellum, the neuronal precursor pool fails to expand normally and the cerebellum is significantly smaller.^[10]

Several different laboratories studying the same protein, now called GAP43, initially used different names. It was designated F1, then B-50, then GAP43, pp46, and finally neuromodulin, each name reflecting a different function of the same molecule.

GAP43, the consensus choice for its designation,[11] is a nervous system-specific protein that is attached to the membrane via a dual palmitoylation sequence on cysteines 3 and 4, though it can exist in the non-bound form in the cytoplasm. This dual sequence enables the association of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] or PIP2, with actin, facilitating the latter's polymerization thereby regulating neuronal structure. This can occur within a lipid raft so as to compartmentalize and localize motility of filopodia in growth cones in developing brains, and could also remodel presynaptic terminals in adults in an activity-dependent manner. GAP-43 is also a protein kinase C (PKC) substrate. Phosphorylation of serine-41 on GAP-43 by PKC regulates neurite formation, regeneration, and synaptic plasticity.^[8]

Because of the association and potential binding of GAP43 with a number of different molecules, including PKC,

Humans with a deletion in one allele of the GAP43 gene fail to form telencephalic commissures and are intellectually disabled.^[12][13]

References